Chan Christine L, Shirley Bezerra Meghan, Stefanovski Darko, Gallop Robert J, Walega Rachel, Donaldson Scott H, Frederick Carla A, Freedman Steven D, Gelfond Daniel, Hoffman Lucas R, Narkewicz Michael R, Rowe Steven M, Sagel Scott D, Schwarzenberg Sarah Jane, Solomon George M, Stalvey Michael S, Kelly Andrea
Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO.
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA.
J Clin Endocrinol Metab. 2024 Dec 9. doi: 10.1210/clinem/dgae857.
Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective therapy that improves lung disease in people with cystic fibrosis (pwCF), but its effect on glucose tolerance and insulin secretion is unclear.
PROMISE is a multicenter prospective, observational study of ETI in pwCF ≥12 years and at least one F508del allele. The PROMISE Endocrine sub-study (PROMISE-ENDO) enrolled participants at 10 CF Centers where hemoglobin A1c (HbA1c) was collected and 3-hour oral glucose tolerance tests (OGTT) conducted to examine glucose tolerance, glucose excursions, insulin secretory rates (deconvolution of C-peptide) and sensitivity (oral minimal model) prior to ETI and 12-18 months (mos) and 24-30 mos following ETI initiation. Longitudinal mixed effects models were used to test within-subject ETI effects.
At baseline, 79 participants completed OGTTs [39 (49%) male, median (IQR) age 19.6 (14.7, 27.3) years, BMI z-score 0.12 (-0.51, 0.65)]. At 12-18 mos n=68 and at 24-30 mos n=58 completed OGTTs. At 24-30 mos, fasting glucose (mg/dL) decreased [94 (92, 96) to 90 (88, 93), p=0.02] in the subset not on insulin therapy (n=61), but no differences in 1-hr or 2-hr glucose were found. HbA1c (%) decreased from 5.8 (5.6, 5.9) to 5.5 (5.4, 5.6), p<0.001 by 24-30 mos. Although insulin sensitivity (mU/L-1.min-1) decreased [8.4 (7.2, 9.5) vs. 6.8 (5.8, 7.9), p=0.03], no changes in oral disposition index were found, p=0.14.
After two years of ETI, fasting glucose and HbA1c showed modest decreases. Glucose tolerance varied, and overall measures of insulin secretion did not deteriorate.
依列卡福妥/替扎卡福妥/依伐卡托（ETI）是一种高效疗法，可改善囊性纤维化患者（pwCF）的肺部疾病，但其对葡萄糖耐量和胰岛素分泌的影响尚不清楚。
PROMISE是一项针对年龄≥12岁且至少携带一个F508del等位基因的pwCF患者进行的ETI多中心前瞻性观察研究。PROMISE内分泌子研究（PROMISE-ENDO）在10个囊性纤维化中心招募参与者，收集糖化血红蛋白（HbA1c）并进行3小时口服葡萄糖耐量试验（OGTT），以在ETI治疗前、ETI开始后12 - 18个月（月）和24 - 30个月时检查葡萄糖耐量、血糖波动、胰岛素分泌率（C肽反卷积）和敏感性（口服最小模型）。采用纵向混合效应模型来测试受试者体内ETI的效果。
基线时，79名参与者完成了OGTT [39名（49%）男性，年龄中位数（IQR）为19.6（14.7，27.3）岁，BMI z评分0.12（-0.51，0.65）]。在12 - 18个月时，n = 68名参与者完成了OGTT，在24 - 30个月时，n = 58名参与者完成了OGTT。在24 - 30个月时，未接受胰岛素治疗的亚组（n = 61）空腹血糖（mg/dL）有所下降[从94（92，96）降至9
